Pseudomonas aeruginosa is the predominant respiratory tract pathogen in patients with cystic fibrosis. Once such patients acquire a Pseudomonas aeruginosa infection, the infection is rarely, if ever, eradicated and a progressive pulmonary deterioration is initiated, ultimately leading to death. In one study, chronic colonization established in the first five years of life was associated with a 20% survival to 16 years of age, whereas 95% of the patients who remained uncolonized in the first five years of life survived to 16 years of age (1). Although the extraordinary predisposition of CF patients to colonization and infection with P. aeruginosa has been recognized for many years, a satisfactory explanation for this phenomenon remains elusive.
Cystic fibrosis is common among caucasians, affecting approximately 1 in 2,000 newborns (2). The mode of inheritance is generally autosomal recessive, suggesting that about 5% of the normal population carries the defective gene. Unfortunately, there are currently no treatments that have resulted in the complete eradication or prevention of Pseudomonas aeruginosa infections in cystic fibrosis patients.
Antimicrobial therapy using antibiotics has been used in several therapeutic protocols. However, the complications that have been observed in antibiotic therapy include the following. Firstly, patients with CF dispose of antimicrobial agents more rapidly than do normal individuals, a phenomenon that mandates therapy with higher doses than those normally recommended. Secondly, strains of Pseudomonas aeruginosa dissociate into multiple phenotypic forms and often with different antimicrobial susceptibility patterns. Thirdly, since the infection is chronic and the infecting strains of Pseudomonas aeruginosa are eradicated rarely, resistance to multiple antimicrobial agents develops frequently. Fourthly, therapeutic levels of antimicrobial agents in sputum are difficult to achieve because of poor penetration and inactivation. Fifthly, the mucoid exopolysaccharide of mucoid strains appears to present a barrier to penetration of some antibiotics. Finally, allergy to certain antibiotics (such as betalactam) renders therapy with antibiotics difficult in some patients.
Anti-inflammatory agents have also been tried in the therapy of Pseudomonas aeruginosa infections in CF patients as it has been postulated that host-mediated inflammation may be responsible for a large part of the pulmonary damage in the CF lung. Efforts have been made to dampen the inflammatory response in the CF lung by use of a systemic steroidal anti-inflammatory therapy using prednisone (3). Unfortunately, prednisone therapy carries substantial risks including growth retardation, glucose intolerance and development of cataracts (4). Preliminary studies are underway to use non-steroidal anti-inflammatory agents.
Therefore, there is a need to provide a therapy for the prevention and eradication of Pseudomonas aeruginosa infections in patients with cystic fibrosis. Therapy to certain diseases has been moving away from classical drug therapy due to adverse drug side effects, to immunotherapies which involve inducing a natural immune response to the pathogen. It is known that phagocytic cells of the immune system (in particular, the lung macrophages) are of critical importance in the host's defence against infections with Pseudomonas aeruginosa. Therefore, it is desirable to understand the mechanism whereby macrophages phagocytose Pseudomonas aeruginosa in order to better understand the dynamics of the host-parasite relationship in cystic fibrosis lung infections and possibly develop a therapy which involves inducing or boosting the response of the lung macrophage to Pseudomonas aeruginosa.
It is known that strains of P. aeruginosa from patients with cystic fibrosis are susceptible to phagocytosis by human neutrophils and macrophages in the absence of serum opsonins (5).